Bioabsorbable granular porous bone filling material and production method thereof

ABSTRACT

A bioabsorbable granular porous bone filling material having a particle diameter 100 to 3000 μm used for filling a defect part after removing a lesion, or grafting a self bone, and for reinforcing or filling a jawbone when embedding a dental implant, is produced such that the polymer material containing a particle-shaped material and having the small hole structure with the hole diameter of 5 to 50 μm is made by mixing the particle-shaped material having a diameter of 100 to 2000 μm with a solution, where the bioabsorbable polymer is dissolved with an organic solvent, the particle-shaped material being not dissolved with this organic solvent but dissolved with a liquid not dissolving the bioabsorbable polymer, freezing it, drying it to remove the organic solvent, pulverizing the produced material, dissolving the particle-shaped material with the liquid to be removed, and sieving it.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a bioabsorbable granular porous bonefilling material and a production method thereof. This material is usedfor filling a defect part after removing a lesion due to osteoma,osteomyelitis or the like and after grafting a self bone, and also usedfor reinforcing, filling or the like of a jawbone at the time ofembedding a dental implant.

2. Description of the Conventional Art

As an artificial bone material, an inorganic material, such ashydroxyapatite ceramics, tricalcium phosphate ceramics, a calciumphosphate-based glass or the like, has been conventionally used. As ashape of the artificial bone material, a rod or block shape is general,but a granular shape is also widely used for filling the defect part, asthis granular shape can be filled to details of the defect part, andapplied to an arbitrary-shaped defect part.

As a bone filling material for filling the defect part, a granularmaterial obtained by pulverizing the above-mentioned inorganic material(for example, refer to Japanese Patent Laid Open No. 1994-339519,2002-58735, 2004-24319) has been used. However, although the inorganicmaterial, such as the hydroxyapatite ceramics or the like, is a similarcomponent of the bone, it has a problem that a foreign substance remainsin a body since it is a nonabsorbable material with respect to a livingbody.

A bone filling material originating in an animal, such as ademineralized freeze dried cow bone allograft or the like, is used inaddition to the inorganic material. However, although the bone fillingmaterial originating in the animal has excellent bio-compatibility, ithas a problem in safety with respect to an unknown pathogen when it isused as a medical supply with respect to a human body. Such an unknownpathogen is represented by BSE (bovine spongiform encephalopathy).

For solving these problems, it can be considered to use a bioabsorbable(hereinafter, it is also said to as a biodegradable) polymer materialwhich exists for bone filling until the bone tissues is reproduced, andis absorbed by the living body to disappear when the reproducing of thebone tissues is finished. However, even when a biodegradable polymerblock is only pulverized to make the granular bone filling material, theabsorption to the living body takes time beyond the need in many cases,and this problem cannot be solved by only changing the diameter of thegranule.

Then, a material with a porous structure called as a foam type, a spongetype or the like provided with many holes having a diameter of about 180to 500 μm in the biodegradable polymer material to increase theabsorption efficiency to the living body, is also used (for example,refer to Japanese Patent Laid Open No. 2002-20523, 2002-146084).However, the conventional production method of the biodegradable polymermaterial having the porous structure is to produce the material in amold having a certain size, so that there are problems that only a blockin the foam type, the sponge type or the like, is produced, and thus thegranular material cannot be obtained. That is, since the block shapedmaterial is a soft material having the porous structure, there is atechnical limit for making it fine at the medical treatment place, andthe infection possibility is also increased. Further, it is very hard toindustrially pulverize the biodegradable polymer material which is thesoft material having the porous structure, and the yield in pulverizingis remarkably low.

Furthermore, since these biodegradable polymer materials are used forthe tissue engineering by mostly seeding a living cell, there is aproblem that these materials are too soft for filling material andinferior in shaping property, for the reason that these materials havethe porous structure in the form type or the sponge type with the holeshaving about 180 to 500 μm diameter, which are larger than the sizes ofthe cell.

SUMMARY OF THE INVENTION

The objective of the present invention is to provide a bioabsorbablegranular porous bone filling material and the production method thereofto solve the problems in the above-mentioned conventional techniques.The bioabsorbable granular porous bone filling material comprises thebioabsorbable polymer material, which has a small hole structure havinga hole diameter of 5 to 50 μm, and has a particle diameter of 100 to3000 μm for easily carrying out the filling operation to the defect partof a patient.

The earnest work was carried out in order to solve the above-mentionedproblems and, as a result of this, the followings were found out tosolve the above-mentioned problems. The bioabsorbable polymer materialhaving the hole diameter of 5 to 50 μm can be obtained effectively bythe process comprising, freezing a solution, where the bioabsorbablepolymer is dissolved with an organic solvent and drying it to remove theorganic solvent. Further, the bioabsorbable polymer material, which isthe soft material having a porous structure, can be industriallypulverized to have the particle diameter of 100 to 3000 μm effectivelyby the processes of approximate-uniformly mixing a particle-shapedmaterial having a desired diameter can be dissolved in the liquid whichdoes not dissolve the bioabsorbable polymer with the solution, where thebioabsorbable polymer is dissolved with an organic solvent, and makingthus produced polymer material into the hard material as compared withthe bioabsorbable polymer material having the conventional porousstructure, by freezing and drying and after pulverizing to produce thebioabsorbable granular porous bone filling material having the particlediameter of 100 to 3000 μm. Then, the present invention is completed.

That is, the present invention relates to the bioabsorbable granularporous bone filling material comprising the bioabsorbable polymermaterial which has the small hole structure having the hole diameter of5 to 50 μm, and has a particle diameter of 100 to 3000 μm and theproduction method of the bioabsorbable granular porous bone fillingmaterial having the particle diameter of 100 to 3000 μm, comprising,approximate-uniformly mixing a particle-shaped material having aparticle diameter of 100 to 2000 μm with the solution, where thebioabsorbable polymer is dissolved with an organic solvent, freezing it,drying it, removing thus the organic solvent, thereby, to produce thepolymer material which has the small hole structure having the holediameter of 5 to 50 μm and contains the particle-shaped material,pulverizing it, dissolving it in a liquid to remove the particle-shapedmaterial, and passing it through the particle diameter sorting apparatussuch as sieve, where the particle-shaped material cannot be dissolvedwith the organic solvent but can be dissolved with the liquid which doesnot dissolve the bioabsorbable polymer.

In the bioabsorbable granular porous bone filling material and theproduction method thereof, as for the bioabsorbable polymer for thepolymer material, it is preferable to select at least one kind frompolyglycolic acid, polylactic acid, a copolymer of lactic acid andglycolic acid, poly-ε-caprolactone, a copolymer of lactic acid andε-caprolactone, polyamino acid, polyortho ester, and a copolymer ofthose. Further, it is preferable that the weight average molecularweight of the bioabsorbable polymer is 5000 to 2000000.

Further, in the production method of the bioabsorbable granular porousbone filling material, it has been found out that at least one kindselected from chloroform, dichloromethane, carbon tetrachloride,acetone, dioxane, and tetrahydrofuran is preferably used for the organicsolvents, that a water-soluble organic and/or inorganic salt ispreferably used for the particle-shaped material, that water ispreferably used for the liquid which dissolves the particle-shapedmaterial and does not dissolve the bioabsorbable polymer, and that theconcentration of the bioabsorbable polymer to the organic solvent ispreferably 1 to 20 wt. %, and the concentration of the particle-shapedmaterial to the organic solvent is preferably 1.0 to 1.5 g/cm³ at thetime of producing the polymer material.

The bioabsorbable granular porous bone filling material according to thepresent invention comprises the soft material having porous structure,which is hardly pulverized in general, but is a new bioabsorbablegranular porous bone filling material, which has a particle diameter foreasily carrying out the filling operation to the defect part of apatient.

Further, the production method of bioabsorbable granular porous bonefilling material according to the present invention is the method forefficiently producing the bioabsorbable granular porous bone fillingmaterial, in which the conventional polymer material having the porousstructure is impossible to be pulverized because of being the softmaterial. Further, the produced bioabsorbable granular porous bonefilling material has the high bioabsorbency, since it has the small holestructure as compared with the conventional bone filling material, whichis produced by pulverizing the block of the bioabsorbable polymermaterial not having the hole to make the granular material.

BRIEF EXPLANATION OF DRAWINGS

FIG. 1 is a scanning electron microscope photograph of a bioabsorbablegranular porous bone filling material produced in Example 1.

FIG. 2 is a scanning electron microscope photograph of a bioabsorbablegranular porous bone filling material produced in Example 4.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

In the present invention, the bioabsorbable polymer for thebioabsorbable granular porous bone filling material is safe for theliving body, and can keep the shape in the body during a fixed period.Further, when the solution dissolving the particle-shaped material,which is mentioned below, does not have solubility for the polymer, thepolymer can be used without especial limitation. For example, at leastone kind selected from polyglycolic acid, polylactic acid, a copolymerof lactic acid and glycolic acid, poly-ε-caprolactone, a copolymer oflactic acid and ε-caprolactone, polyamino acid, polyortho ester, and acopolymer of those can be used. In these materials, polyglycolic acid,polylactic acid, and the copolymer of lactic acid and glycolic acid arethe most preferable since these are recognized from U.S. Food and DrugAdministration (FDA) as the polymer being harmless to a human body, andhave actual results. It is preferable that the weight average molecularweight of the bioabsorbable polymer is 5000 to 2000000, and morepreferably 10000 to 500000.

In the method of the present invention, the bioabsorbable polymer isdissolved with the organic solvent in the producing process. While theorganic solvent is used suitably selecting with the polymer material tobe used, at least the one kind selected from chloroform,dichloromethane, carbon tetrachloride, acetone, dioxane, andtetrahydrofuran is preferably used in general. In the dissolvingprocess, a heat treatment or an ultrasonic treatment may be usedtogether. While the concentration of the bioabsorbable polymer is notlimited especially if this polymer can be dissolved uniformly in theorganic solvent, preferable concentration is 1 to 20 wt. % in theorganic solvent.

In the method of the present invention, the particle-shaped materialhaving the particle diameter of 100 to 2000 μm is approximate-uniformlymixed with the organic solvent in which the bioabsorbable polymer isdissolved, in the producing process. This particle-shaped material isnot dissolved with the organic solvent in which the bioabsorbablepolymer is dissolved and is dissolved with the liquid which does notdissolve the bioabsorbable polymer. The particle-shaped material canexist in the solid state in the polymer material, until the polymermaterial is pulverized to become the granular material. The polymermaterial is produced by approximate-uniformly mixing the particle-shapedmaterial with the solution in which the bioabsorbable polymer isdissolved, freezing it, drying it, and removing the organic solventThus, the polymer material contains the particle-shaped material and hasthe small hole structure having the hole diameter of 5 to 50 μm.Further, the particle-shaped material can be rapidly dissolved andremoved with the liquid, which does not dissolve the bioabsorbablepolymer, after pulverizing. The polymer material becomes hard since theparticle-shaped material exists in the solid state (the particle state)in the polymer material, so that the pulverization becomes easy, andthus, the granule having the arbitrary particle diameter can be easilyproduced.

As the method for approximate-uniformly mixing the particle-shapedmaterial with the organic solvent in which the bioabsorbable polymer isdissolved, there is a method of adding the particle-shaped material intothe organic solvent in which the bioabsorbable polymer is dissolved,stirring and mixing it if necessary, and taking it into a mold, a methodof pouring the organic solvent in which the bioabsorbable polymer isdissolved into a mold where the particle-shaped material is already putin, or a method of pouring the particle-shaped material into a moldwhere the organic solvent in which the bioabsorbable polymer isdissolved is already put in.

It is necessary that the particle diameter of the particle-shapedmaterial is 100 to 2000 μm, and an aggregated granular crystallineparticle may be used if it is a crystalline material. If the particlediameter of the particle-shaped material is less than 100 μm, the sizeof the polymer among the particle-shaped materials in the producedpolymer material becomes small, so that the yield in pulverizing thepolymer material having the objective particle diameter of 100 μm ormore may be decreased. If the particle diameter is more than 2000 μm,the amount of the particle-shaped materials in the produced polymermaterial is increased, so that the yield in pulverizing may bedecreased. It is more preferable that the particle diameter of theparticle-shaped material is 200 to 1000 mm.

Further, it is preferable that the blending amount of theparticle-shaped material to the organic solvent in which thebioabsorbable polymer is dissolved is 1.0 to 1.5 g/cm³. If the blendingamount is less than 1.0 g/cm³, the effect for hardening the producedpolymer material is hardly obtained. If this amount is more than 1.5g/cm³, the ratio of the polymer in the produced polymer material isdecreased, so that the production yield may be decreased. Morepreferably, the blending amount is 1.0 to 1.25 g/cm³.

As for the particle-shaped material used in the present invention, it isnot limited especially if this material has the characteristic that thematerial is not dissolved with the organic solvent in which thebioabsorbable polymer is dissolved, and dissolved with the liquid whichdoes not dissolve the bioabsorbable polymer. However, preferableparticle-shaped material are water soluble organic and/or inorganicsalts like an inorganic salt such as sodium chloride, potassiumchloride, calcium chloride or the like, an ammonium salt such asammonium chloride or the like, or an organic salt such as citric acidtrisodium or the like, because these materials can use cheap water asthe liquid which does not dissolve the bioabsorbable polymer. Sodiumchloride, potassium chloride and citric acid trisodium are especiallypreferable as these particle-shaped materials are easily available andhave little damage to a human body.

In the method of the present invention, the polymer material containingthe particle-shaped material and the small hole structure having thehole diameter of 5 to 50 μm is produced by approximate-uniformly mixingthe particle-shaped material with the solution of the bioabsorbablepolymer being dissolved with the organic solvent, freezing it using afreezer or liquid nitrogen, drying it, and removing the organic solvent.However, the operation for removing the organic solvent changes with theorganic solvent. For example, if the solvent is an organic solventhaving high volatility, the solvent is only kept at the roomtemperature, but the solvent is dried under a reduced pressure using avacuum dryer in general.

In the method of the present invention, the bioabsorbable granularporous bone filling material having the particle diameter of 100 to 3000μm is obtained by pulverizing the polymer material, removing theparticle-shaped material by dissolving it with the liquid which does notdissolve the bioabsorbable polymer, and passing it through the sieve. Atthis time, although a method for removing the particle-shaped materialchanges with the material, if the water soluble organic and/or inorganicsalt such as the sodium chloride, the potassium chloride, the calciumchloride, the ammonium chloride, the citric acid trisodium or the likeis used as mentioned above, the material can be removed easily andsafety with water.

In this case, the reason why the particle diameter of the bioabsorbablegranular porous bone filling material is 100 to 3000 μm is thefollowing. If the particle diameter is less than 100 μm, the particlediameter is too small, so that the bone forming is prevented by a slightmovement phenomenon caused by the filling material being not stable andnot fixed at the filling part. Further, a phagocytic cell such as aforeign body giant cell or the like eats the bioabsorbable granularporous bone filling material having the small diameter to cause theinflammatory reaction. Thus, it is not preferable. If the particlediameter is more than 3000 μm, a space among the bioabsorbable granularporous bone filling materials becomes large, so that an epithelial cellor the like invades into the space in the bioabsorbable granular porousbone filling material before the bone reproduction. Thus, it is notpreferable.

EXAMPLE 1

The polymer material containing the sodium chlorideapproximate-uniformly was obtained, by adding the copolymer of lacticacid and glycolic acid (lactic acid: glycolic acid=75:25, the weightaverage molecular weight was about 250000) into dioxane to have theconcentration of 12 wt. %, stirring it by a stirrer to dissolve it,approximate-uniformly mixing a sodium chloride powder (a particlediameter was 300 to 700 μm) with the dioxane solution of the copolymerof lactic acid and glycolic acid being dissolved to have the sodiumchloride concentration of about 1.18 g/cm³, pouring it into a mold,freezing it under the condition of −30° C. by a freezer (MDf-0281AT madeby Sanyo Electric Corporation), and drying it under a reduced pressurefor 48 hours by a vacuum dryer (DP43 made by Yamato ScientificCorporation) to remove the dioxane. Then, the bioabsorbable granularporous bone filling material was obtained at the yield of about 86%, bycutting the polymer material to become small pieces, pulverizing thesmall pieces by a planetary ball mill for 50 minutes, taking thepulverized polymer material into a flask, adding a distilled water tothe flask, stirring it for 1 hour to remove sodium chloride, moving itto a petri dish, drying it by the vacuum dryer for 48 hours, and passingit through a sieve. This bioabsorbable granular porous bone fillingmaterial had the particle diameter of 300 to 700 m, and had the averagehole diameter of about 5 μm. The scanning electron microscope photographof this bioabsorbable granular porous bone filling material is shown inFIG. 1.

EXAMPLE 2

The polymer material containing the sodium chlorideapproximate-uniformly was obtained, by adding the polyglycolic acid (theweight average molecular weight was about 200000) into dichloromethaneto have the concentration of 9 wt. %, stirring it by the stirrer todissolve it, pouring the dichloromethane solution of polyglycolic acidbeing dissolved into a mold where the sodium chloride powder (theparticle diameter was 300 to 700 μm) was already put in to have sodiumchloride concentration of about 1.18 g/cm³, freezing it under thecondition of −30° C. by the freezer (MDf-0281AT made by Sanyo ElectricCorporation), and drying it under a reduced pressure for 48 hours by thevacuum dryer (DP43 made by Yamato Scientific Corporation) to removedichloromethane. Then, the bioabsorbable granular porous bone fillingmaterial was obtained at the yield of about 80%, by cutting the polymermaterial to become small pieces, pulverizing the small pieces by theplanetary ball mill for 20 minutes, taking the pulverized polymermaterial into a flask, adding the distilled water to the flask, stirringit to remove sodium chloride, moving it to the petri dish, drying it bythe vacuum dryer for 48 hours, and passing it through the sieve. Thisbioabsorbable granular porous bone filling material had the particlediameter of 700 to 1400 μm, and the average hole diameter of about 20μm.

EXAMPLE 3

The polymer material containing the potassium chloride uniformly wasobtained, by adding the copolymer of lactic acid and glycolic acid(lactic acid: glycolic acid=75:25, the weight average molecular weightwas about 250000) into dioxane to have the concentration of 12 wt. %,stirring it by the stirrer to dissolve it, pouring the dioxane solutionof the copolymer of lactic acid and glycolic acid being dissolved intothe mold where a potassium chloride powder (the particle diameter wasabout 400 μm) is already put in to have the potassium chlorideconcentration of about 1.08 g/cm³, freezing it under the condition of−30° C. by the freezer (MDf-0281AT made by Sanyo Electric Corporation),and drying it under a reduced pressure for 48 hours by the vacuum dryer(DP43 made by Yamato Scientific Corporation) to remove dioxane. Then,the bioabsorbable granular porous bone filling material was obtained atthe yield of about 86%, by cutting the polymer material to become smallpieces, pulverizing the small pieces by the planetary ball mill for 50minutes, taking the pulverized polymer material into the flask, addingthe distilled water to the flask, stirring it to remove potassiumchloride, moving it to the petri dish, drying it by the vacuum dryer for48 hours, and passing it through the sieve. This bioabsorbable granularporous bone filling material had the particle diameter of 300 to 700 μm,and the average hole diameter of about 20 μm.

EXAMPLE 4

The polymer material containing the citric acid trisodium was obtained,by adding the poly-(L)-lactic acid (the weight average molecular weightwas about 250000) into dichloromethane to have the concentration of 6wt. %, stirring it by the stirrer to dissolve it, approximate-uniformlymixing a citric acid trisodium powder (the particle diameter was about200 to 500 μm) with the dichloromethane solution of the poly-(L)-lacticacid being dissolved to have the concentration of about 1.02 g/cm³,pouring it into the mold, freezing it under the condition of −30° C. bythe freezer (MDf-0281AT made by Sanyo Electric Corporation), and dryingit under a reduced pressure for 48 hours by the vacuum dryer (DP43 madeby Yamato Scientific Corporation) to remove dichloromethane. Then, thebioabsorbable granular porous bone filling material was obtained at theyield of about 84%, by cutting the polymer material to become smallpieces, pulverizing the small pieces by the planetary ball mill for 20minutes, taking the pulverized polymer material into the flask, addingthe distilled water to the flask, stirring it to remove citric acidtrisodium, moving it to the petri dish, drying it by the vacuum dryerfor 48 hours, and passing it through the sieve. This bioabsorbablegranular porous bone filling material had the particle diameter of 700to 1400 μm, and the average hole diameter of about 25 μm. The scanningelectron microscope photograph of this bioabsorbable granular porousbonefilling material is shown in FIG. 2.

1. A bioabsorbable granular porous bone filling material comprising, a bioabsorbable polymer material having a small hole structure where a hole diameter is 5 to 50 μm, and having a particle diameter of 100 to 3000 μm.
 2. The bioabsorbable granular porous bone filling material as claimed in claim 1, wherein a bioabsorbable polymer for the polymer material is at least one kind selected from polyglycolic acid, polylactic acid, a copolymer of lactic acid and glycolic acid, poly-ε-caprolactone, a copolymer of lactic acid and ε-caprolactone, polyamino acid, polyortho ester, and a copolymer of those.
 3. The bioabsorbable granular porous bone filling material as claimed in claim 1, wherein a weight average molecular weight of the bioabsorbable polymer is 5000 to
 2000000. 4. A production method of the bioabsorbable granular porous bone filling material, the method comprising, approximate-uniformly mixing a particle-shaped material having a particle diameter of 100 to 2000 μm with a solution, where the bioabsorbable polymer is dissolved with an organic solvent, the particle-shaped material being not dissolved with said organic solvent but dissolved with a liquid which does not dissolve the bioabsorbable polymer, freezing it, drying it to remove said organic solvent to produce the polymer material containing the particle-shaped material and having the small hole structure where the hole diameter is 5 to 50 μm, pulverizing said produced polymer material, dissolving said particle-shaped material with the liquid to be removed, where the liquid does not dissolve the bioabsorbable polymer, and passing it through a sieve to produce the bioabsorbable granular porous bone filling material having the particle diameter of 100 to 3000 μm.
 5. The production method of the bioabsorbable granular porous bone filling material as claimed in claim 4, wherein at least one kind selected from polyglycolic acid, polylactic acid, a copolymer of lactic acid and glycolic acid, poly-ε-caprolactone, a copolymer of lactic acid and ε-caprolactone, polyamino acid, polyortho ester, and a copolymer of those, is used as the bioabsorbable polymer.
 6. The production method of the bioabsorbable granular porous bone filling material as claimed in claim 4, wherein a polymer having the weight average molecular weight of 5000 to 2000000 is used as the bioabsorbable polymer.
 7. The production method of the bioabsorbable granular porous bone filling material as claimed in claim 4, wherein at least one kind selected from chloroform, dichloromethane, carbon tetrachloride, acetone, dioxane, and tetrahydrofuran is used as the organic solvent.
 8. The production method of the bioabsorbable granular porous bone filling material as claimed in claim 4, wherein a water soluble organic and/or inorganic salt is used as the particle-shaped material, and water is used as the liquid which dissolves the particle-shaped material and does not dissolve the bioabsorbable polymer.
 9. The production method of the bioabsorbable granular porous bone filling material as claimed in claim 4, wherein the polymer material is produced by making the concentration of the bioabsorbable polymer of 1 to 20 wt. % and the concentration of the particle-shaped material of 1.0 to 1.5 g/cm³, with respect to the organic solvent. 